Neurophysiological Consequences of Addictive Disorders
Drug abuse endures as one of the major public health problems in the United States, and throughout the world. One of the core features of addictive disorders, in laboratory animals as well as in humans, is that drugs of abuse are acutely reinforcing and produce intense drug craving following chronic exposure. Behavioral and pharmacological studies have implicated the mesolimbic dopamine system (containing the ventral tegmental area [VTA] and its projections, e.g., the nucleus accumbens [NAc]) in the acute reinforcement and craving seen with opiates, cocaine, alcohol, and other drugs of abuse. An important goal of research in this area is to identify changes that drugs of abuse produce in this neural pathway that account for the intense craving seen with chronic drug use, and more critically, to identify factors that can inhibit or reverse these changes to the neural pathway.
Over the past several years, studies have identified a series of common and specific actions of opiates, cocaine, and alcohol on the mesolimbic dopamine system (see, Nestler et al., 1993, Neuron 11:995-1006). In the VTA, these actions include increased levels of tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), and decreased levels of neurofilaments. In the NAc, these actions include decreased levels of the inhibitory G protein, Gi.alpha., and increased levels of adenylyl cyclase and cyclic AMP-dependent protein kinase. Increasing direct evidence now supports a role for these various biochemical adaptations in the behavioral actions of drugs of abuse mediated via the mesolimbic dopamine system.
The finding of increased levels of glial filaments, and reduced levels of neurofilaments, in the VTA suggests that a major form of plasticity, perhaps even neural injury, occurs in this brain region during the course of chronic drug exposure. This possibility is further supported by the observation that chronic morphine or cocaine administration reduces axoplasmic transport, specifically from the VTA to the NAc (see, Nestler et al., supra).
These observations hint at the possibility that neurotrophins could possibly modify the actions of drugs of abuse on the mesolimbic dopamine system. However, there is no certainty that this is the case. Accordingly there is a need in the art to determine whether one or more neurotrophic factors can modify the actions of drugs of abuse on the brain physiology. There is a further need to identify the neurotrophin or neurotrophins, if any, that are capable of demonstrating this activity.
In a preliminary report of the present inventors (Beitner-Johnson et al., 1993, Soc. Neurosci. Abst. 19:663), various neurotrophic factors were infused via osmotic minipumps into the VTA of rats over a 10 day period. Rats were implanted with subcutaneous morphine or placebo pellets on days 5-10. Animals were sacrificed on day 11, and levels of TH, GFAP, and NFs were determined in the VTA by immunoblotting. It was found that chronic infusion of BDNF alone prior to morphine administration exerted effects opposing morphine on TH and GFAP levels. In contrast, infusion of IGF-I and CNTF prior to morphine administration exerted effects similar to those of morphine on TH and GFAP in the VTA, and NT-3 influence these proteins in a different pattern. BDNF infusion was found to decrease the ability of chronic morphine to regulate these proteins in the VTA as well as to up-regulate the cAMP pathway in the NAc, a major projection area of the VTA. These observations of changes in the VTA require confirmation in behavioral studies before reaching any firm conclusion regarding the ability of BDNF, or any neurotrophic factor, to counter the neurophysiological changes that accompany addiction in vivo. It also remained uncertain whether BDNF could affect the expression of TH and GFAP in the VTA remedially, i.e., whether this (or any) neurotrophin could reverse the changes associated with an addictive disease or disorder. Thus, there is a need in the art to determine whether the neurophysiological changes to the VTA observed in addictive diseases cause or influence the observed behavioral changes, and to demonstrate that a neurotrophin or neurotrophins that oppose the physiological changes can reverse or oppose the corresponding behavioral changes.